The invention is directed to implantable radiotherapy devices, and particularly to devices which can be made radioactive after being formed to a desired final or near-final shape
Tumors, stenoses of biological conduits, and other proliferative tissue can be effectively treated with radiation, which is known to inhibit cellular proliferation. The mechanism by which radiation prevents such proliferative cellular response is by preventing replication and migration of cells and by inducing programmed cell death (apoptosis).
Cells are variably susceptible to radiation, dependent on the types of cells and their proliferative status. Rapidly proliferating cells are generally more radiation-sensitive, whereas quiescent cells are more radiation-tolerant. High doses of radiation can kill all functions of even quiescent cells. Lower levels can merely lead to division delays, but the desirable effect of reproductive death is still obtained. In this case, the cell remains structurally intact but has lost its ability to proliferate, or divide indefinitely.
Traditional high-dose external beam radiation treatment, and prolonged low dose rate, close-distance radiation treatment (brachytherapy), are well-established therapies for the treatment of cancer, a malignant form of cellular proliferation. In particular, attention is currently being directed to the practical aspects of the use of brachytherapy. These aspects are, of course, particularly significant when radioactivity is involved. A disease site in a patient may be exposed to radiation from an external beam, either as a stand-alone procedure or in conjunction with an operative procedure. Alternatively, the radioactivity may be incorporated into an implantable device. In the first case, a higher energy radiation source is used to achieve the necessary penetration of radiation into the tissue to be treated. As a result, other organs or tissue may be unnecessarily exposed to radiation, and safety, handling and logistics problems arise. In the second case, the implantable devices are typically quite expensive. In particular, if radioactivity is added to the source, the source may only be effective for radiotherapy during a relatively short period during which the radioactivity is provided at a useful (therapeutic) level. Depending on the radioisotope used, the decay time may be as short as hours, days or weeks.
The current state of the art brachytherapy for treatment of localized lesions such as tumors of, for example, the prostate, breast, brain, eye, liver, or spleen, employs radioactive, xe2x80x9csealed sourcexe2x80x9d seeds. The term xe2x80x9csealed sourcexe2x80x9d, as used herein, means that radioisotopes incorporated into a device are integral with the device and cannot be dislodged or released from the host material of the device in the environment of usage. A typical sealed source seed includes a radiation source encapsulated within an impermeable, biocompatible capsule made of, for example, titanium, which is designed to prevent any leaching or release of the radioisotope. The seeds are approximately the size of a grain of rice (typically 0.81 mm in diameter by 4.5 mm long) and are implanted individually at a treatment site within and/or around a lesion, typically with a medium bore (18-gauge) delivery needle.
Disadvantages of the use of such seeds as radiotherapy devices include their nature as discrete, or point, sources of radiation, and the corresponding discrete nature of the dosages which they provide. In order to provide an effective radiation dose over an elongated or wide target area, the seeds should be uniformly and relatively closely spaced. The need to ensure accurate and precise placement of numerous individual radiation sources undesirably prolongs the surgical procedure, and hence the exposure of the surgical team to radiation. Moreover, the use of discrete seeds requires an elaborate grid matrix for their proper placement. This requirement is labor-intensive, and therefore costly. In addition, the discrete nature of the seeds renders them more susceptible to migration from their intended locations, thereby subjecting portions of the lesion, the treatment site, and surrounding healthy tissue to over- or under-dosage, reducing the effectiveness and reliability of the therapy.
Other disadvantages exist in radioactive seed therapy. Relatively few radionuclides are suitable for use in sealed-source seeds, because of limited availability of radioisotopes with the necessary combination of half-life, specific activity, penetration depth and activity, and geometry. In addition, the implantation of seeds generally requires a delivery needle with a sufficiently large bore to accommodate the seeds and may, in some cases, require an additional tubular delivery device. The use of a relatively large delivery needle during seeding may cause unnecessary trauma to the patient and displacement of the lesion during the procedure. Also, because of the risk of migration or dislodgement of the seeds, there is the risk that healthy tissues near or remote from the lesion site will be exposed to radiation from seeds which have become dislodged from their intended locations and possibly carried from the body within urine or other fluids. In addition, radioactive seed therapy is inadequate for treating certain types of intraluminal tissue proliferation, such as, for example, stenosed coronary arteries, and therefore a need exists for more suitable radiotherapy devices for such intraluminal brachytherapy applications.
Radiotherapy devices made of palladium-103 are desirable because palladium-103 has a half life of about 17 days and a photon energy of 20.1-23 KeV, which makes it particularly suitable for use in the treatment of localized lesions of the breast, prostate, liver, spleen, lung and other organs and tissues. Because palladium-103 is unstable and not naturally occurring in the environment, it must be manufactured, generally either by neutron activation of a palladium-102 target, or by proton activation of a rhodium target. In the neutron activation process, a palladium-102 isotope is exposed to a neutron flux in a nuclear reactor to convert palladium-102 to palladium-103. The efficiency of this conversion is dependent on the neutron flux and the duration of the bombardment in the reactor. The palladium-103 thus formed is fabricated into radioactive seeds. This approach is disclosed in, for example, U.S. Pat. No. 4,702,228 to Russell, Jr. et al.
The neutron activation approach is prohibitively expensive, as the natural abundance of palladium-102 is less than one percent. Enrichment of this isotope to even 20% levels is very costly. In addition, the utility of this process is unsatisfactory, as other isotopes of palladium and other elements, as well as impurities, may be formed and/or activated in the process and can alter or otherwise interfere with the desired radiation.
In the proton activation process, a rhodium-103 target is provided which is irradiated with a proton beam to transform a portion of the rhodium to palladium-103. This process requires that the rhodium-103 target be cooled and then irradiated until a sufficient amount of palladium-103 is obtained to enable chemical separation of the palladium from the rhodium. The rhodium target is then immersed in a strong acid to separate palladium-103 from rhodium-103. The palladium-103 radionuclides can now be used directly as radiation sources or formed into compounds-for later use. This material is generally absorbed into or otherwise incorporated into a non-radioactive carrier material which is then placed into a non-radioactive secondary container, such as a titanium can or shell, and sealed to form a radioactive seed. The secondary container may include some type of radiopaque marker to allow it to be radiographically visible. This approach is disclosed in, for example, U.S. Pat. No. 5,405,309 to Carden, Jr.
The proton activation approach also has disadvantages. Each step of the process requires a wet chemistry separation to isolate palladium-103 from rhodium-103, and each of these steps has a yield loss associated with it. The disadvantages of discrete seeds in brachytherapy applications have already been discussed.
U.S. Pat. No. 5,342,283 to Good discloses multi-layer radioactive microspheres and wires which are made by forming concentric radioactive and other coatings on a substrate. The radioactive coatings are made by various deposition processes, including ion plating and sputter deposition processes, as well as via exposure of an isotope precursor, such as palladium-102, to neutron flux in a nuclear reactor. The radioactive wires may have nonuniform distributions of radioactivity over their surfaces, as needed for a particular treatment.
A disadvantage of the Good radioactive devices is that they cannot be made economically or simply. As previously mentioned in connection with the creation of palladium-103 from palladium-102 using neutron flux, such processes are prohibitively expensive and require lengthy and costly wet chemistry separation steps to isolate the radioactive isotope from the non-radioactive precursor. Further, the coating methods disclosed by Good for making radioactive coatings are relatively complicated, multistep processes which are difficult to control. In addition, the multiple coatings of the Good devices may detach, deteriorate, flake, spall, peel, leach or otherwise degrade with time and/or exposure to bodily fluids, resulting in dissemination of radioactive and other materials into the body, with potentially harmful consequences.
It would therefore be an advancement in the art to provide a general purpose radiotherapy device which can be relatively easily and economically fabricated.
An object of the present invention is to provide a general purpose radiotherapy device which can be used to deliver a wide variety of radiation treatments.
Another object of the present invention is to provide a general purpose radiotherapy device which obviates the disadvantages of the prior art radiotherapy seeds and similar devices.
Another object of the present invention is to provide a general purpose radiotherapy device which can be fabricated to a desired net or near-net size and shape, and all or a portion of the device rendered radioactive in a relatively simple one-step activation process, without lengthy chemical separation steps to isolate the radioactive species from its nonradioactive precursor material.
And another object of the present invention is to provide a general purpose radiotherapy device made of a transmutable material which can be made radioactive upon exposure to an accelerated beam of charged particles.
Still another object of the invention is to provide a general purpose radiotherapy device which is made of a material which can be fabricated to net or near-net shape while in a non-radioactive state, and then made radioactive, and further formed or finished as needed in a radioactive state.
Another object of the invention is to provide a general purpose radioatherapy device which can be either temporarily or permanently implanted in a patient to deliver radiation in situ.
Still another object of the invention is to provide a general purpose radiotherapy device which provides radiation in a dose and distribution pattern that can be tailored or customized to any particular therapy requirement during fabrication and activation of the device.
Another object of the invention is to provide a general purpose radiotherapy device which emits radiation in a pattern that can vary over the length or breadth of the device and is not dependent solely on the shape of the device.
The radiotherapy device of the present invention provides an effective alternative to encapsulated radioactive seeds or sandwiched structures. The nature of the radiotherapy device disclosed herein allows it to be fabricated to virtually any desired net or near-net size and shape while it is in a non-radioactive state, and then all or a portion of the device rendered radioactive in a single activation step. The device can then be implanted into a patient either temporarily or permanently, with minimal loss of radioactivity and minimal radiation exposure to others. Alternatively, the device can be formed to an intermediate or near-net shape while in a non-radioactive state, and then all or a portion of the device made radioactive, and then the device can be formed as needed to a final shape while in a radioactive state.
The use of accelerated beam technology to make all or a portion of the device radioactive after it has been formed to net or near-net shape lowers the unit cost of the device, allows greater flexibility in the design and use of the device, and eliminates the need for laborious wet chemistry separation procedures. The device can be made to net or near-net shape in a variety of geometries, and all or any portion of the device can be made radioactive, so that it can be used in a wide variety of applications. Other advantages will be detailed more fully below.
According to the invention, there is provided a radiotherapy device for in situ delivery of radiation to a treatment site in a patient. At least a portion of the device is made of a transmutable material which is transformable to a radioisotope-containing material upon activation by an accelerated beam of charged particles. At least the transmutable portion of the device is formed to at least near-net shape.
The charged particles preferably have an energy of at least about 4 MeV and are preferably selected from the group consisting of protons, deuterons and alpha particles.
In a preferred embodiment, the transmutable material comprises rhodium and the radioisotope-containing material contains palladium-103. The transmutable portion of the device is formable either to a desired net shape prior to activation, or to a desired near-net shape prior to activation and to a desired net shape after activation, i.e., while in a radioactive state.
The device preferably emits radiation in a pattern having a shape which is determined at least in part by the distribution of the radioisotope-containing material on the surfaces of the transmutable portion of the device and not solely by the shape of the device. In one embodiment, the distribution of radioisotope-containing material is substantially constant; in another embodiment, it is variable.
In one embodiment, the device is in the form of an elongated element which can be substantially solid or tubular. The elongated element preferably has an aspect ratio of at least 3 to 1. In one preferred embodiment, the elongated element is in the form of a wire. The wire can include a transmutable portion at one or both ends thereof or at any intermediate portion. The elongated element can be formed into any two-dimensional or three-dimensional shape, such as a zig-zag or helix.
In another embodiment, the device is in the form of a two-dimensional sheet or a three-dimensional shape. In one preferred embodiment, the device is in the form of a spherically contoured plaque having a concave surface and a convex surface. At least a portion of the concave surface is activatable and includes palladium-103.
In still another embodiment, the device is in the form of a seed.
The source may be partially of a non-transmutable material which is preferably selected from the group consisting of non-transmutable metals, nonmetals, polymers and composite materials.
The device can further include a substantially radiation-transparent encapsulating material which is applied to at least a portion of the surface of the device. Alternatively, or additionally, the device can include a substantially radiation-transparent, non-radioactive agent applied to at least a portion of the surface of the device. The non-radioactive agent is preferably selected from the group consisting of therapeutic agents and lubricating agents.
The device can further include a radiopaque marker to make it visible under x-rays.
In one embodiment, the device is adapted for surgical fastening of tissue at a wound repair site and is preferably a device such as, for example, a staple, suture, clip, pin, nail, screw, plate, barb, anchor, or patch.
The device can be adapted for either temporary or permanent placement within the patient and may include one or more anchors suitable for such purpose.
According to another aspect of the invention, there is provided a method of delivering radiation in situ to a treatment site in a patient. The method comprises the steps of:
a. Providing a radiotherapy device which is at least partially made of a transmutable material which is transformable to a radioisotope-containing material upon activation by an accelerated beam of charged particles, at least the transmutable portion being formed to at least near-net shape;
b. Activating the transmutable portion of the device with a beam of charged particles at sufficient energy to form the radioisotope-containing material; and
c. Placing the device at the treatment site in the patient so that the treatment site is exposed to the radioisotope-containing material.
The method can include the further step of forming the transmutable portion of the device to a desired net shape prior to activation, or to a desired near-net shape prior to activation and to a desired net shape after activation. In addition, the method can include the step of activating the transmutable portion of the device so that the device emits radiation in a pattern having a shape which is determined at least in part by the distribution of radioisotope-containing material on the surfaces of the transmutable portion of the device and not solely by the shape of the device. This distribution can be either substantially constant or variable. The method can include the further step of applying a substantially radiation-transparent encapsulating material to at least a portion of the surface of the device. In addition, or alternatively, the method can include the step of applying a substantially radiation-transparent, non-radioactive agent to at least a portion of the surface of the device. A radiopaque marker can also be incorporated into the device.
According to still another embodiment of the invention, a kit for delivering in situ a predetermined dose of radiation to a treatment site in a patient comprises a general purpose radiotherapy device, as described above, and a delivery vehicle for placing the device into the patient. In a preferred embodiment, the device is in the form of an elongated element and the delivery vehicle is a syringe or catheter.